The overall objective of this study is to determine the virologic and immunologic parameters of early HIV infection that correlate with surrogate markers of HIV disease progression. This project will characterize the pathogenesis of acute, primary HIV infection in a large, prospective cohort of high risk individuals in India, where heterosexual transmission of non-subtype B HIV-1 has been documented. We propose to focus our investigation of this hypothesis on the following question. Does the viral specific cytolytic T lymphocyte (CTL) response correlate with surrogate markers of disease progression following acute, primary HIV infection? CTL directed against HIV-1 env, gag and nef antigens during primary infection will be quantitated. In addition, CTL activity directed against subtype specific and cross- reactive gp160 targets will be assessed using a novel recombinant vaccinia expressing subtype c env. Characterization single cell CTL clones directed against subtype specific and cross-reactive gp160 targets will include identification of HLA restriction and minimal peptide epitopes. The development of HIV proviral quasispecies diversity in the HIV env,gag and nef genes during primary infection will be measured using heteroduplex analysis. These parameters will be correlated with two surrogate markers of disease progression (plasma viral load and CD4+Tcell count). This study will also address the question of whether the CTL response to primary HIV infection, directed against specific HIV antigens, results in sufficient immunologic pressure to select for the early development of proviral quasispecies diversity. This proposal is a collaboration between the National AIDS Research Institute (NARI) in India, the Johns Hopkins University (JHU) and the Laboratory of Immunoregulation (LIR), National Institute of Allergy and Infectious Diseases, NIH. The study site in Pune, India has been selected due to the expected enrollment of more than 30 individuals per year with documented acute, primary HIV infection, including 15-20 subjects per year, enrolled during the preseroconversion window period, the recent heterosexual transmission of multiple non-B HIV subtypes in this cohort and inclusion of both symptomatic and asymptomatic individuals. We believe that this proposal will address some of the limitations of previous studies of acute, primary HIV infection and will provide new and important information about the pathogenesis of HIV infection, disease progression and new insights important for HIV vaccine development.